Gastric cancer (GC) is one of the most common malignancies worldwide, and a variety of histological subtypes have been reported recently [1]. Signet ring cell carcinoma (SRC) is a rare adenocarcinoma subtype, which is found commonly in the stomach and occasionally in the breast, ovary, colon, rectum, and gallbladder [2]. SRC exhibits abundant intracellular mucin in more than 50% of tumor cells, presenting a seal ring. The incidence of GC has declined since the advent of Helicobacter pylori eradication treatments. However, the incidence of gastric SRC has been rising in recent years. In fact, SRC currently accounts for approximately 15%–28% of GC, and this percentage is still increasing [3]. On the other hand, prognosis of gastric SRC in early stage has been reported in all studies as equivalent to or better than that of other gastric adenocarcinomas (non-SRC) [4]. However, in advanced GC, prognosis of gastric SRC is more controversial and is commonly considered to be poorer than that of non-SRC. Furthermore, available evidence suggests that gastric SRC is considered to be less chemosensitive than non-SRC [56]. In addition, gastric SRC tends to present with advanced tumor stage and lymph node involvement, hence it is characterized by a lower resection rate and a higher recurrence rate [7]. Due to poor patient responses in cytotoxic therapies and a low rate of curative resection, a unique multimodal treatment plan for gastric SRC in advanced stages is urgently required. However, international clinical practice guidelines do not recommend any special treatment for SRC. Postoperative radiotherapy (RT) is the standard treatment for locally advanced GC (stage II/III) [89]. In 2 retrospective studies [1011] and one case report [12], preoperative RT improved survival outcomes of rectal SRC, especially in stage III SRC. To understand whether RT has potential clinical value for SRC, we examined data from a population-based cancer database (Surveillance, Epidemiology, and End Results [SEER]) with the aim to assess the impact of postoperative RT on patients with stomach SRC by using propensity score matching (PSM).

In recent years, although the incidence of GC has decreased, the incidence of gastric SRC is still increasing [1920]. The incidence of GC is closely related to H. pylori infection; therefore, the decline in the incidence of GC is attributed to H. pylori eradication. However, the link between gastric SRC and H. pylori remains unclear. The World Health Organization classifies gastric SRC as diffuse GC characterized by rapid progression towards gastric adenocarcinoma [212223]. At the molecular level, the expression of E-cadherin encoded by the CDH1 gene is decreased, resulting in lack of adhesion between cells, potentially leading to increased rate of metastasis [2324]. For a long time, the histological type of SRC has been considered as an independent predictor of poor prognosis [252627], but this view has been questioned in recent years. In fact, progression of SRC is related to the advanced stage at the onset of the disease, and SRC does not show worse prognosis after correction for stage [6]. Several studies have reported that the survival rate of patients with early gastric SRC is better than that of patients with non-SRC. However, a meta-analysis of 35,947 cases of GC (including SRC) in 19 centers showed that the prognosis of advanced SRC was worse than that of non-SRC [24]. In most studies, SRC was found to be more advanced, which may explain poor prognosis [28]. Our results showed a higher proportion (56.8%) of stage III patients with poorer prognosis than stage II patients, which is consistent with previous studies.

There are still controversies regarding resection of lymph nodes. The European Society for Medical Oncology recommends that more than 16 lymph nodes should be assessed to avoid misinterpretation of TNM staging [29]. Smith et al. [30] explored the effect of the total number of surgically removed lymph nodes on stage-specific survival rate in 3,814 patients with GC. This study showed that the survival rate increased significantly as the NLNE increased. However, excessive removal of lymph nodes can damage the immune system, leading to a range of other clinical problems, such as increased susceptibility to infection. Our study showed that OS and tumor-specific survival improved when the NLNE in patients with stage II and III gastric SRC was greater than 15

In addition, there are different perspectives regarding other prognostic factors. Lu et al. [31] found that older age and advanced tumor stage were independent predictors of poor OS, while tumor location and chemotherapy regimen were not associated with prognosis. Analysis of SRC subgroups showed that prognosis was not related to sex, stage, and chemotherapy. In contrast, other studies revealed that sex, age, tumor size, location, and TMN staging are important factors that influence prognosis of SRC [2832]. This inconsistency may be due to staging methods, geographic and medical differences. Our Cox regression analysis and nomogram showed that age, ethnicity, number of lymph node dissection, tumor location and size, and TNM staging were independent prognostic factors for gastric SRC, and were closely related with the 3-, 5-, and 10-year survival rates.

GC usually manifests as late stage disease, and thus adjuvant treatment is regularly recommended before or after surgery. A few landmark trials have shown that over time, the positive effects of adjuvant treatments are becoming more apparent. The Intergroup 0116 (INT 0116) trial was the first major randomized trial to demonstrate a survival benefit for fully resected GC patients with adjuvant chemoradiotherapy (CRT) [33]. The Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial showed a positive prognostic effect in patients treated with surgery followed by chemotherapy (epirubicin, cisplatin, and fluorouracil) compared with surgery alone in a Western cohort [34]. INT-0116 and MAGIC were severely criticized for inadequate lymph node dissection in a significant number of eligible patients. Therefore, in these trials adjuvant treatment is considered merely as replacement for inadequate surgery in Western GC patients. However, the results of INT-0116 were confirmed in a non-randomized trial in a cohort of D2-resected Eastern patients [35]. A recent meta-analysis determined that adjuvant RT in resectable GC increased OS and CSS by 20% [36]. The Adjuvant Chemoradiation Therapy in Stomach Cancer (ARTIST) [37] study investigated whether the addition of RT to capecitabine/cisplatin- adjuvant CT after D2 radical surgery is beneficial for the survival of patients with GC. After using RT, the 5-year OS of GC patients was not improved (CT vs. CRT, 73% vs. 75%), but subgroup analysis showed that lymph node-positive and intestinal GC patients may benefit from radiation therapy [38]. Subsequent ARTIST2 [39] mainly aimed to determine whether addition of RT to adjuvant CT improves survival in GC patients with lymph node-positive D2 radical surgery. The authors found that adjuvant CT or CRT improved effectively disease-free survival (DFS) in patients with pathologically-staged II or III, node-positive, D2-resected GC. However, no difference in DFS between CT and CRT (HR, 0.910; P=0.667) was observed. Regarding gastric SRC, ARTIST and INT-0116 showed a low chemo-radiation effect in the diffuse type that included SRC. However, Heger et al. [7] found that although patients with gastric SRC responded poorly to neoadjuvant chemotherapy, they showed better prognosis. Their study showed that radiation therapy can improve prognosis of SRC in locally advanced esophageal cancer. Other studies [1011] have shown that preoperative RT improved survival of patients with colorectal signet ring cell cancer (especially stage III). However, Asano et al. [40] reported that a 58-year-old woman with mucosa-associated lymphoid tissue (MALT) lymphoma developed gastric SRC after radiation therapy. MALT was related to the occurrence of GC, suggesting that careful consideration should be given to treatment of MALT lymphoma. Similarly, RT has been reported very rarely in gastric SRC. A study of 194 cases of gastric SRC (45%), 124 of which (64%) were operated after RT and 70 (36%) were operated without RT, showed no significant difference in early (pT1) survival rates between the 2 groups [41]. In our study, after PSM calibration, postoperative chemotherapy did not improve patient survival, but postoperative RT significantly improved OS (P=0.001) and tumor-specific survival (P=0.003) in advanced-staged SRC. In most adenocarcinomas, radiosensitivity is related to the degree of cell differentiation; the higher the degree of differentiation, the lower the radiosensitivity. In adenocarcinoma, SRC is usually poorly differentiated. Therefore, RT should be, in theory, more effective for SRC than for non-SRC patients. Moreover, anti-epidermal growth factor receptor (EGFR) drugs improved sensitivity of RT [42] and expression of EGFR in colorectal SRC was negative/low [43]. We speculate that RT should be more effective for SRC than for non-SRC patients. However, only a few studies examining the mechanisms of RT in SRC have been performed. In future studies, we should focus on the mechanisms of RT in SRC, both in vitro and in vivo.

Although the design and analysis of our study is rigorous, it still has several limitations. First, the SEER database lacks important information, such as centralized pathological reviews, quality of surgical operation, details of chemotherapy and RT, pathological response to RT, uniformity in treatment, conditions of local and distant recurrence, and further treatment of complications. Second, it is only a database-based case-control study with inevitably missing data, thus deliberate practice is required. Therefore, multi-center RCT studies with long-term follow-up are required to verify our conclusions.